29: Principles of Local Anesthetic

Question 1

What do all local Anesthetics have In common? (What is their very gross MOA?)

Answer 1

Drugs which reversibly block neuronal conduction when applied locally

Question 2

Recap: How is a neural AP generised?

Answer 2

1. Na+ channels open–> Na+ influx leads to depolerisation
2. Na+ channels close, K+ channels open leading to K+ efflux and repolierisation
3. too far: hyperpolerisation
4. Restored to normal

Question 3

Summarise the common structural characteristics of local anesthetics

Answer 3

All have 3 things in common

• aromatic region (for benzine-like properties)
• central ester/amide bond
  
  • defines the two classes of LA
• Basic amine side-chain

Question 4

What are the two Classes of Local Anesthetics?

Name an example for each

Answer 4

Determined by the bond that links the aromatic ring and amine side chain

1. Esters (e.g. Cocaine)
2. Amides (e.g. Lidocaine)

Question 5

What are hte different MOA of local Anesthetics

Answer 5

1. Mainly: Hydrophilic pathway
2. But also: Hydrophobic pathway
3. might also influenct channel gating
   
   • prolong inactive state of sodium channels

Question 6

Explain the Hydrophilic pathway in the MOA of local Anesthetics

Answer 6

1. Unionised form of LA diffuses across
   
   • connective tissue membrane
   • axonal membrane
2. Gets ionised intracellulary
3. Ionised form goes into open Na+ channel and blocks it from the inside
4. No Exitation of Neuron

Question 7

Explain the use-dependancy of LAs

Answer 7

Use dependant because

• Hydrophilic pathway works by entering channels in open form
• is nocioceptors are more active–> more open channels

Question 8

Explain the Hydrophobic MOA of LA

Answer 8

Minor role (mainly Hydrophilic)

• lipid soluble LA diffuse in membrane and directly block NA+ channels from membrane

Question 9

What are the cellular effecs of an LA?

Answer 9

• prevents generation and conduction of AP
• No direct influence on resting membrane potential
• might influence channel gating
  
  • leave Na+ channels inactivated for longer

Question 10

Explain the selectivity of LA

Answer 10

It has the main effects on

• small diameter fibres (e.g. A delta and C-firbes)
• non-myleinated fibres (easier to access)
  
  • generally: good effect on sensory fibres and only limited effect on motor nerves

Question 11

Name the different ROA for LA

Answer 11

1. Topical (Surface Anaesthesia)
2. Infiltration Anaesthesia
3. IV regional Anaesthesia
4. Nerve block Anaesthesia
5. Spinal Anaesthesia
6. Epidural Anaesthsia

Question 12

What are the sites, formulation and concentration of Surface anaesthesia in the use of LA

Answer 12

1. Expecially on Mucosal Surfaces (e.g. mouth, bronchial tree)
2. Spray or powder
3. high concentration needed –> risk of systemic toxicity

Question 13

What is the mechanism and indication of Infiltration anaesthesia in the administration of LAs

Answer 13

• Directly into tissues → sensory nerve terminals
  
  • often Adrenaline co-injection
    
    • causes vasoconstriction which limits dosage, risk of systemic toxicity and bleeding
    • (NOT extremities (e.g. digits) to avoid ischaemia
• Used in Minor surgery

Question 14

How would you administer LA in Intravenous regional anaesthesia?

What are the implications and risks?

Answer 14

• i.v. administration distal to pressure cuff
• E.g. in Limb surgery
• Systemic toxicity in premature cuff release

Question 15

Explain the Mechanism and use of Nerve block anaesthesia in the application of LAs

Answer 15

• Close to nerve trunks e.g. dental nerves
• Widely used – low doses required
• but: slow onset
• Vasoconstrictor co-injection

Question 16

Explain the

• site of injection
• use and
• side effects of

A spinal anaesthesia use in administration of LA

Answer 16

• Site of injection: subarachnoid space –> around spinal routes
• Low dose
• uesd in surgeries of Abdomen, pelvis,

Question 17

Explain the side effects of a spinal anaesthesia use in administration of LA

Answer 17

• ↓ b.p. –> due to block of preganglionic SNS fibres
• prolonged headache
  
  • due to LA goint via CSF into brain

Question 18

Why might Glucose be added to a LA in a spinal anaesthesia?

Answer 18

To increase its specific gravity

• gives better control over effect due to its distribution via tilting table

Question 19

Where is an Epidural anaesthesia administered?

What are its advantages and disadvantages compared toa spinal anaestesia?

Answer 19

Administerd in fatty tissue in epidural space

• has same indication + childbirth but also
  
  • slower onset of action
  • higher doses that are required (increased risk of systemic toxicity)
• Advantages
  
  • more resticted action
  • less effect on BP decrease

Question 20

What are the Pharmacokinetic properties of most LAs?

Answer 20

E.g. Lidocaine (Amide)

• good absorbtion in mucus membrane
• weak base
• 70% Plasma protein bound
• t 1/2 and Duration of action 2h

Question 21

What is the Metabolism of Lidocaine?

Answer 21

Hepatic

N-dealkylation (split of of alkyl group)

Question 22

Why is more LA required in infected tissue?

Answer 22

Becaue infected tissue is acidic

• LA are weak bases
• more ionised and less able to get into nerves
• higher dose needed

Question 23

What are the Pharmacokinetic properties of Cocaine when used as an LA?

Answer 23

• good absorbtion over mucus membranes
• 90% plasma protein bound
• t 1/2 about 1h
  *

Question 24

Explain the metabolism of Cocaine

Answer 24

Metabolised in Liver and plasma by

Non-specific esterases

Question 25

What are the Side effects of most LA on the CNS ?

Answer 25

Paradox effects at low doses (at high doses depressant but)

• stimulation
• restlessness, confusion
• tremor

–> possibly due to inhibition of GABA neurons

Question 26

What are the side effects of Lidocaine (and most LA) on the CVS?

Answer 26

• myocardial depression
• vasodilatation
• ↓ b.p.

Due to Na+ block —> less exitation

Question 27

What are the Side effects of Cocaine used as an LA?

Answer 27

Overall: caused not by NA+ block but by SNS stimmulation (inhibited reuptake)

• CNS
  
  • euphoria, exitation
• CVS
  
  • increased CO
  • vasoconstriction
  • increase in BP

Question 28

Which LA is often used in epdiural of spinal anaesthesia?

Why?

Answer 28

Bupivacaine

due to longer duration of action (doa about 6hr)